Polylactic acid-based implant susceptible of bioresorption containing and antibiotic

ABSTRACT

Implantable poly(lactic acid)-based pharmaceutical composition which comprises at least one water soluble antibiotic in particle form with controlled dimensions, less than 100 μm uniformly dispersed in an amorphous poly(lactic acid) matrix, said composition being in ground powder or thin film form. Application especially in initiating local internal antibiotic therapy by the gradual release of the antibiotic substance.

The subject of the present invention is an implantable and bioresorbablepharmaceutical composition based on poly(lactic acid), intendedespecially for implementing a local internal antibiotherapy.

It is known that the pharmaceutical industry is currently looking fornew implantable medicinal forms, which progressively release the activeprinciple, with the aim of overcoming the faults of the conventionalpharmaceutical forms and in particular of avoiding the necessity forrepeated administrations.

Controlled-release systems are generally micro-capsules, microspheres orbulk implants of various forms, for example cylindrical forms (needles).In these systems, the active principle is generally dispersed in abioresorbable polymer matrix.

Among bioresorbable polymers, poly(lactic acid)s are the most used. Theliterature provides varied examples of application of such systems,especially to anti-cancer chemotherapy and to hormonotherapy.

In the field of antibiotherapy, poly(lactic acid) microspherescontaining erythromycin have already been described. These microspheresare administered by parenteral injection and act systemically, withprogressive release of the antibiotic, while reducing irritation of thetissues at the point of injection; see P. K. Gupta et al., 5th Congr.Int. Technol. Pharm., 4, 73-79, 1989.

However, microspheres do not constitute a satisfactory form ofadministration, on the one hand because they contain residues ofsurface-active agents used in their preparation and, on the other hand,because they generally contain a thin polymer layer at the surface whichis free of active substance, which at first delays the release of thissubstance.

The subject of the present invention is an implantable pharmaceuticalcomposition intended in particular for implementing a not general, butlocal, antibiotherapy, essentially restricted to sites of operations, inorder to prevent and/or cure local infections which must always befeared after a surgical operation.

Systemic antibiotherapy with broad-spectrum antibiotics administeredparenterally is currently used to prevent these infections. Thedisadvantages of general antibiotherapy are known: painful injectionwith irritation of tissues, renal or hepatic toxicity and the necessityfor repeated administrations.

The subject of the present invention is to overcome these disadvantagesby making available to the surgeon a bioresorbable composition, intendedto be implanted at the site of operation, before suturing the wound andmaking it possible to implement a local internal antibiotherapy byprogressive release of the antibiotic substance. Of course, thebioresorbable composition of the invention, intended to provide a localantibiotherapy affecting the site of operation, is mainly deployed incontact with soft internal tissues accessible via the wound. It can alsobe placed on the contact surface between a bulk bone implant (especiallyosteosynthesis component) and the bone cavity intended to receive thisimplant.

For ease of such a use, the composition of the invention is provided inthe form of a powder or thin film. The powder is a powder obtained bygrinding a dispersion of the antibiotic in the polymer matrix, whichmakes it possible to avoid the disadvantages, indicated above, of themicrospheres.

In fact, it has been discovered that compositions in the ground powderor thin film form make it possible to obtain a satisfactory releaseprofile, with an initial phase of rapid and strong release (or "burst")of the antibiotic present at the surface, making it possible to obtain asuitable attack dose, followed by a phase of slower release of theantibiotic over a sufficiently long period of time, for example aboutten days.

In the compositions of the invention, degradation of the polymer matrixis relatively slow with respect to the period of release of theantibiotic, in order that this release is controlled bydissolution/diffusion phenomena of the antibiotic in the externalmedium, and not as a result of the degradation of the matrix.

Another characteristic of the compositions of the invention is that theantibiotic is added in the form of particles having controlled sizes,which makes it possible to better control the reproducibility and theduration of the release phenomenon of the antibiotic.

One advantage of the compositions of the invention is that, as will beshown hereinbelow, by the choice of the molecular masses of the polymermatrix, of the concentration of the antibiotic and of the size of theparticles in the case of powders, or alternatively by the combination ofpowders having different characteristics, it is possible to adapt and tovary the release profiles of the antibiotic as desired.

The subject of the present invention is thus an implantable andbioresorbable pharmaceutical composition based on poly(lactic acid),intended for implementing a local internal antibiotherapy, characterizedin that it comprises at least one water-soluble antibiotic in the formof particles of controlled sizes, dispersed homogeneously in anamorphous poly(lactic acid) matrix, and in that the said composition isprovided in the form of a ground powder or a thin film.

In the composition of the invention, the antibiotic particles aredistributed homogeneously (randomly), which differentiates them from themicrospheres, for example, as already indicated above.

These antibiotic particles have sizes of less than 100 μm, and inparticular of between 0.01 and 50 μm.

The Applicant have discovered that an important condition for obtaininga homogeneous dispersion and a suitable release of the active substancein a poly(lactic acid) matrix is that of using an amorphous poly(lacticacid), because the semi-crystalline polymer matrices lead to excessivelyfast releases of the active substance and to excessively lengthydegradation times of the polymer.

For this, it is advisable to use a polymer consisting of a mixture ofunits derived from D- and L-lactic acids, the proportions of each of theD- and L-units being sufficient for the matrix to be amorphous. It ispossible to use, in particular, amorphous poly(lactic acids) which areobtained when from 20 to 80% of the units which they contain areD-lactic units (the other units being, of course, L-lactic units). It ispossible, in particular, to use polymers obtained starting from racemicmodifications of D,L-lactic acid, or of D,L-lactide, in order to obtainamorphous polymers containing equal proportions of the two types ofunits.

Another subject of the invention is a process for the preparation of acomposition as defined above. This process is characterized in that thesaid antibiotic particles and the said poly(lactic acid) are mixed so asto obtain a homogeneous dispersion and then in that, according to knownmethods, the dispersion obtained is put into the form of a ground powderor thin film.

According to a first embodiment, the composition of the invention isprovided in the form of a powder obtained by grinding a homogeneousdispersion of the antibiotic in an amorphous poly(lactic acid) matrixhaving a molecular mass at least equal to 10,000, in particular at leastequal to 30,000. In fact, polymers having an excessively low molecularmass are not suitable for being used on their own: they have a tendencyto give, with the antibiotic, either pasty products or powders in whichthe release profiles of the antibiotic are less suitable because theylead, in particular, to an excessively fast release of the activesubstance.

The molecular mass of the amorphous poly(lactic acid)s used according tothe invention in the manufacture of ground powders is generally between10,000 and 200,000, and preferably between 20,000 and 300,000.

Of course, this is a mean molecular mass, measured, for example, by gelpermeation chromatography in dioxane with respect to polystyrenestandards.

It is known that poly(lactic acid)s of relatively high molecular massescan be obtained, in particular, by lactide polymerization, for exampleby polymerization of D,L-lactide. There also exist usable high molecularmass poly(lactic acid)s which are commercial products.

In order to prepare the dispersion of the antibiotic in the polymer, itis possible, for example, to mix the antibiotic particles in the polymerin a solvent of the polymer in which the antibiotic is insoluble. Afterobtaining a dispersion of the antibiotic in the solution of the polymer,the solvent is evaporated, for example in a rotary evaporator to promotethe homogeneity of the dispersion. The mass obtained is then ground, soas to obtain a powder having, for example, particle sizes between 0.1and 1 mm.

By virtue of this process, in which dissolution followed byreprecipitation of the antibiotic is avoided, it is possible to controlthe sizes of the antibiotic particles in the powders obtained.

The ground powder obtained can then, if desired, be sieved to obtainpowders having the desired particle size.

Liberation studies of the antibiotic substance, in an isotonic phosphatebuffer of pH 7.4 at 37° C. have shown that the rate of release of theantibiotic increases when the sizes of the particles of the compositiondecreases. It is optionally possible to benefit from this phenomenon byusing a mixture of at least two sets of particles having different meansizes. The small particles will make possible the rapid release of anattack dosage of the antibiotic, whereas the bigger particles will givea sustained release of antibiotic. For example, a mixture of particleshaving sizes of 0.1 to 0.2 mm with particles having mean sizes of 0.5 to1 mm, in suitable proportions, will be used.

The liberation studies have also shown that the rate of release of theantibiotic increases with the proportion of antibiotic contained in thepowder. It is thus possible, for a powder having given mean sizes, tochoose the concentration of the antibiotic so as to obtain a suitablerate of release. For example, a powder will be chosen having aproportion of antibiotic sufficient for the amount of antibioticreleased, in an isotonic phosphate buffer of pH 7.4 at 37° C., after 24hours, to be at least equal to 20% of the initial amount of antibioticsand to be less than 70% (in particular less than 50%) of the saidinitial amount.

Generally, in the powders of the invention, the concentration of theantibiotic is between 5 and 30% by weight, and chosen, in particular,depending on the particle sizes of the powder.

Likewise, the liberation studies of the antibiotic in a phosphate bufferhave shown that the rate of release of the antibiotic decreases when themolecular mass of the poly(lactic acid) increases.

Thus, by using the model of the liberation of the antibiotic in aphosphate buffer, as indicated above, it is possible easily todetermine, by simple routine experiments, the particle sizes of thepowders, the antibiotic concentrations in the said powders and themolecular masses of the poly(lactic acid) which will give the desiredrelease profiles of the antibiotic.

As already indicated above, poly(lactic acid) matrices having lowmolecular masses, in particular less than 10,000, lead to pastes orpowders being obtained which release the antibiotic too rapidly to beable to be used on their own. More precisely, in the case of anamine-containing antibiotic, the antibiotic in the salt form gives apaste with the low molecular mass poly(lactic acid), whereas theantibiotic in the non-salt form gives a powder. For example, the lowmolecular mass poly(lactic acid) described in Example 2 of theexperimental part below, in combination with 10% of gentamycin base,gives a powder which, in a phosphate buffer, releases, over 24 hours,approximately 50% of the antibiotic which it contains, and then thelevel of release of antibiotic is low in the days which follow. Such apowder could not be used on its own but could be used in combinationwith a powder whose poly(lactic acid) matrix has a molecular mass and/ora particle size sufficient for the release of the antibiotic which itcontains to be more progressive.

According to a second embodiment, the composition of the invention isprovided in the form of a thin film. It is possible to obtain thinpoly(lactic acid) films, which can be used according to the invention,by conventional processes for the manufacture of films, especially bymixing an amorphous poly(lactic acid), of high mean molecular mass, forexample greater than 20,000, with an amorphous poly(lactic acid) of lowmean molecular mass, in particular less than 5,000, the latter acting asplasticizing agent. The proportion of poly(lactic) acid of low molecularmass could, in particular, be a proportion sufficient for the glasstransition temperature of the mixture of polymers to be less than apredetermined temperature, for example 37° C. In fact, the glasstransition temperature decreases when the proportion of polymer of lowmolecular mass increases.

The implantable thin films of the invention are, of course, flexiblefilms (or ones capable of rapidly being converted to flexible films oncontact with the body fluids present at the site of implantation), so asto prevent traumatism of the tissues and to adapt to the shape of thesurgical site.

It is possible easily to adjust the flexibility of the film, whichincreases with the content of poly(lactic acid) of low molecular mass.

It is recalled that poly(lactic acid)s having low molecular masses arecommercially available. Amorphous poly(lactic acid)s of low molecularmass can also be obtained according to known methods, in particular bypolycondensation of mixtures of L- and D-lactic acids, for example ofD,L-lactic acid.

The liberation studies of the antibiotic (in a phosphate buffer, asindicated above) from films have shown that, as for the powders, therate of release of the antibiotic increases when the proportion of theantibiotic increases.

These studies have also shown that the rate of release of the antibioticincreases when the proportion of poly(lactic acid) of low molecular massincreases.

It is thus possible to adjust, by simple routine experiments, thesuitable proportions of poly(lactic acid) of low molecular mass and/orof antibiotic to obtain the desired rate of release of antibiotic.

Generally, the proportion of poly(lactic acid) of low molecular mass inthe mixture of polymers will be between 1 and 50% by weight, and inparticular between 5 and 40%.

For a given mixture of polymers, a proportion of antibiotic will bechosen, for example, which is sufficiently high for the amount ofantibiotic released, in an isotonic phosphate buffer of pH 7.4 at 37°C., at the end of 24 hours, to be at least equal to 20% of the initialamount, for a film having an initial thickness of 0.3 mm, the saidproportion of antibiotic being chosen which is sufficiently low for thesaid amount released to be less than 70% of the initial amount.

It is also, or simultaneously, possible to act on the proportions of thepolymers and to choose a proportion of polymer of low molecular masswhich is both sufficiently high and sufficiently low for the amount ofantibiotic released, under the conditions which have just beenindicated, to lie in the range already mentioned.

To prepare a composition in the film form, it is possible to proceed asin the case of the powders, that is to say to mix the particles ofantibiotic and the poly(lactic acid) in a solvent of the polymer inwhich the antibiotic is insoluble and then to evaporate the solvent,preferably slowly so as to avoid formation of surface bubbles. Thepoly(lactic acid) is here the mixture of polymers of high molecular massand of low molecular mass. The thickness of the film can then beadjusted by calendering. It is also possible to mix the antibioticparticles by kneading with the polymer and then to form a film bycalendering.

Films are thus prepared having, for example, a thickness which can varyin the range of 0.05-1 mm.

To promote chemical exchanges, healing of the tissues and bloodcirculation (revascularization) at the site of implantation, it ispossible to convert the film into a perforated film, furnished with aplurality of perforations. The surface area of the perforationsrepresents, for example, from 10 to 70% of the total surface area of thefilm, depending on the thickness of the film. The surface area of theperforations can become larger as the film becomes thicker.

The antibiotic present in the compositions of the invention ispreferably a broad-spectrum antibiotic. It is, however, possible tocombine a number of antibiotics, not only antibacterial but alsoantifungal. Of course, antibiotics will preferably be chosen which arenot, or rarely, allergizing. Mention may for example be made ofaminoglycosides such as gentamycin, tobramycin, amikacin, netilmicin orneomycin; macrolides such as erythromycin; polypeptide antibiotics suchas polymyxin B, bacitracin or gramicidin; lincomycin and itsderivatives, especially clindamycin; rifamycins, in particularrifampicin; tetracyclines; 5-nitroimidazoles such as metronidazole andtinidazole; ketoconazole, nystatin, griseofulvin, amphotericin; or alsofusidic acid (in the soluble salt form), spectinomycin or vancomycin.

The antibiotics often contain amine groups which can form salts. Theantibiotic present in the composition of the invention can be in thefree form or the salt form. The salts are, of course, salts which arecompatible with a pharmaceutical use. Mention will for example be madeof, the sulphates, the hydrochlorides and the like, or also saltsobtained with polyanions, preferably bioresorbable ones, such as thepoly(malic acid) which is described especially in U.S. Pat. Nos.4,265,247 and 4,320,753. Likewise, antibiotics containing carboxylgroups can be used in the form of salts, for example of alkali metal(sodium, potassium) salts.

It should be noted that when an amine-containing antibiotic is not inthe salt form, it can combine with the carboxyl groups of thepoly(lactic acid) (end carboxyl groups or carboxyl groups appearing as aresult of the degradation of the polyacid). Generally, such acombination will have a tendency to reduce the rate of release of theantibiotic and/or to restrict this release.

Another subject of the invention is a process of therapeutic treatmentintended to implement a postsurgical local internal antibiotherapy,characterized in that there is implanted, in the operating cavity, aneffective amount of a composition in the ground powder or thin filmform, as defined above.

The composition of the invention is administered as indicated above,especially in man, by implanting at the end of the surgical operation,before suturing the wound. The doses used are those which make itpossible to obtain release of the antibiotic at effective doses, theseeffective doses being known. It is thus possible to determine, in eachcase, the doses of implantable composition which it is advisable to use(for example using the phosphate buffer study model mentioned above).

Of course, it is possible to combine the use of a composition in thepowder form with a composition in the film form, the composition in thepowder form being chosen, for example, to make possible faster releaseof the antibiotic in the first hours following the implantation.

The following examples illustrate the invention without, however,limiting it.

EXAMPLE 1 Preparation of ground powders

A lactic acid polymer is prepared by polymerization of D,L-lactide. Forthis, a bulk polymerization is carried out, in the presence of 0.05% byweight of zinc, in a sealed round-bottomed flask at 140° C. withstirring, for 3 weeks After cooling, the reaction product is dissolvedin chloroform or acetone and an alcohol (methanol or ethanol) is addedto precipitate the polymer formed, while the residual monomers and thepoly(lactic acid)s of low molecular weight formed remain in solution.The polymer is then dried for one week under vacuum at 40° C.

The polymer obtained has a number-average molecular mass of 160,000 anda weight-average molecular mass of 280,000.

The X-ray diffraction spectrum shows the absence of crystalline domains.

This amorphous polymer has a glass transition temperature, determined bydifferential thermal analysis, of approximately 44° C.

5 g of this polymer are dissolved in 100 ml of acetone. An amount ofgentamycin sulphate is added which is sufficient for the final mixtureto have a gentamycin sulphate content of 10% by weight. The mixture isthen evaporated to dryness using a rotary evaporator and is then driedunder reduced pressure at 40° C.

The dried product is then cryogenically ground (at the temperature ofliquid nitrogen). After grinding, it is in the form of solid particles.Three fractions, having particle sizes respectively between 0.125-0.25mm (small sizes), 0.25-0.5 mm (medium sizes) and 0.5-1 mm (large sizes),are separated by sieving.

The studies of the liberation of the antibiotic in a phosphate buffer,under the conditions indicated above, show that the powders of smallsize release more than 50% of the antibiotic which they contain in 24hours. The release is then very low. The powders of average size releaseapproximately 40% of the antibiotic in 24 hours and approximately 55% inthe first ten days. Particles of large size release 25 to 30% of theantibiotic on the first day, to reach a release of 50% at the end of 10days.

Powders containing respectively 20% and 30% of gentamycin sulphate wereprepared analogously, as well as powders containing one of the followingantibiotics: tobramycin, neomycin, bacitracin, clindamycin andrifampicin.

A powder containing 20% by weight of a poly(malic acid) and gentamycincomplex was also analogously prepared, this complex having been preparedfrom the sodium salt of a poly(malic acid) (MM: 20,000) dissolved inwater, to which an excess of gentamycin sulphate is added.

EXAMPLE 2 Preparation of films

A poly(lactic acid) was prepared in a way analogous to that described inExample 1, with the following characteristics:

M_(n) =170,000

M_(w) =280,000

Glass transition temperature: 35° C.

Absence of crystalline domains.

Moreover, a poly(lactic acid) of low molecular weight was prepared bypolycondensation of D,L-lactic acid at 140° C. under vacuum for 3 days.After cooling, the reaction product is dissolved in acetone and thepolymer is precipitated by addition of water to the solution, while theresidual monomers remain in solution. The polymer is then dried for oneweek under vacuum.

It has the following characteristics:

M_(n) =2,000

M_(w) =2,600

This polymer is in the form of a viscous and sticky paste. Its glasstransition temperature is of the order of 0° C.

As in Example 1, the polymers, in suitable proportions, are dissolved inacetone and a calculated amount of gentamycin sulphate is added. Themixture is then run into a Petri dish coated with Teflon.

The solvent is evaporated at room temperature, under atmosphericpressure, to prevent the formation of surface bubbles. Drying is thencompleted under reduced pressure. Finally, calendering is carried outwith a calender containing chromium-plated rollers.

Films were thus prepared having a thickness of approximately 0.3 mm inwhich the proportion of poly(lactic acid) of low molecular mass is 10,20 or 30% with respect to the total mass of the polymers, these filmscontaining, by weight, 10% or 20% of gentamycin sulphate.

Films were analogously prepared in which the polymer of low molecularmass is a polymer obtained by polycondensation of a mixture of D-lacticand L-lactic acids containing 70% of D-lactic acid.

The studies of the liberation in a phosphate buffer show that the"burst" phenomenon is reduced in the case of films. At the end of 24hours, approximately 20% of the antibiotic is released in the case of amatrix containing 10% or 20% of polymer of low molecular mass, for thefilms containing 10% of gentamycin sulphate. The release of theantibiotic then continues steadily, being faster as the content ofpolymer of low molecular mass is higher. In the case of the matrixcontaining 20% of polymer of low molecular mass, the release of theantibiotic reaches 50% between approximately 20 and 30 days.

Films were analogously prepared containing one of the followingantibiotics: oxytetracycline, doxycycline, erythromycin, metronidazole,ketoconazole, clindamycin and chloramphenicol.

EXAMPLE 3 In vivo study

Implantation of particles

Particles having sizes between 0.5 and 1 mm, containing 10% ofgentamycin sulphate, obtained in Example 1, were implanted in theposterior part of the paravertebral muscle of rabbits at twoimplantation sites per animal, on each side of the vertebral column. Theamounts implanted were 100 mg.

The amount of gentamycin excreted in the urine is regularlyquantitatively determined, according to a method analogous to thatdescribed by Gambardella et al., Journal of Chromatography, 348, 229-240(1985).

The amount excreted is large on the first two days (respectively 2 and 3mg/day on the first and second days) and then decreases slowly until thefifteenth day after implantation.

At the end of 14 days, a small region of necrosis of the muscle tissuesis generally observed at the sites of implantation.

By comparison, gentamycin sulphate implanted alone (10 mg) givesextensive regions of necrosis; urinary excretion is very high on thefirst day (7 mg/day), decreases to 1 mg/day on the second day andbecomes zero on the eighth day.

Implantation of films

The films were implanted, as above, in rabbits, at 75 mg per site ofimplantation.

The films used, obtained as described in Example 2, are mixtures ofpolymers containing respectively 10%, 20% or 30% of the poly(D,L-lacticacid) of low molecular mass, all the films studied containing 10% ofgentamycin sulphate.

This study lasted 10 days.

As in the case of powders, urinary excretion of gentamycin is high onthe first two days and then decreases on the following days. It is stillpresent after 10 days whereas, with gentamycin sulphate implanted alone,it becomes virtually zero on the seventh day. Moreover, the amounts ofantibiotic excreted become larger as the proportion of polymer of lowmolecular mass increases.

On the tenth day, necroses are markedly greater in rabbits which havereceived gentamycin sulphate alone. Additionally, it is noticed that thethickness of the necrosed regions around the implants is approximatelyhalf that of the necrosed regions of the implantation channel, whichsuggest that the necrosis is essentially due to surgical traumatismduring insertion of the films.

In conclusion, the in vivo studies have shown, with the implantablecompositions of the invention, the progressive release of the antibioticafter a more or less strong burst, depending in particular on the natureof the implant.

In vivo studies have generally confirmed the validity of the resultsobtained with the in vitro release model in a phosphate buffer.

The toxicity is less than with gentamycin sulphate implanted alone, andthe tissue reactions are relatively weak, which confirms the excellentbiocompatibility of the implantable compositions of the invention.

We claim:
 1. A bioresorbable pharmaceutical composition comprisingpoly(lactic acid), said composition being implantable so as to implementa local internal antibiotherapy for those in need thereof, saidcomposition comprising an antibiotically effective amount of at leastone water-soluble antibiotic in the form of particles of controlled sizeless than 100 μm dispersed homogeneously in a poly(lactic acid) matrix,said composition being provided in the form of (i) either a groundpowder obtained by grinding a homogeneous dispersion of said antibioticin an amorphous poly(lactic acid) matrix having a mean molecular massranging from 10,000 to 300,000 or (ii) a thin film whose poly(lacticacid) matrix is made of a mixture of (1) an amorphous poly(lactic acid)having a mean molecular mass greater than 20,000 and (2) an amorphouspoly(lactic acid) having a mean molecular mass less than 5,000.
 2. Thepharmaceutical composition of claim 1 wherein said amorphous poly(lacticacid) matrix comprises a mixture of units derived from a D- and L-lacticacid, the amount of each of said D- and L-units being sufficient forsaid poly(lactic acid) to be amorphous.
 3. The pharmaceuticalcomposition of claim 2 wherein said poly(lactic acid) contains from 20to 80 percent of D-lactic units.
 4. The pharmaceutical composition ofclaim 3 wherein said poly(lactic acid) contains units derived from D-and L-lactic acids in equal proportions.
 5. The pharmaceuticalcomposition of claim 1 in the form of a ground powder wherein saidamorphous poly(lactic acid) matrix has a molecular mass at least equalto 10,000.
 6. The pharmaceutical composition of claim 1 in the form of aground powder wherein said amorphous poly(lactic acid) matrix has amolecular mass ranging from 10,000 to 30,000.
 7. The pharmaceuticalcomposition of claim 1 wherein said ground powder has a particle sizeranging from 0.1 to 1 mm.
 8. The pharmaceutical composition of claim 7wherein said ground powder comprises a mixture of (a) particles having asize ranging from 0.1 to 0.2 mm and (b) particles having a size rangingfrom 0.5 to 1 mm.
 9. The pharmaceutical composition of claim 8 whereinthe concentration of said antibiotic is sufficient for the amount ofantibiotic released, in an isotonic phosphate buffer of pH 7.4 at 37°C., at the end of 24 hours, to be at least equal to 20 percent of theinitial amount of antibiotic and less than 70 percent of the initialamount.
 10. The pharmaceutical composition of claim 9 wherein the amountof said antibiotic ranges from 5 and 30 percent by weight.
 11. Thepharmaceutical composition of claim 1 wherein the amount of saidamorphous poly(lactic acid) having a molecular mass less than 5,000 issufficient for a glass transition of said mixture of polymers being lessthan 37° C.
 12. The pharmaceutical composition of claim 1 wherein theamount of the water-soluble antibiotic or the low molecular masspoly(lactic acid) or mixture thereof is sufficiently high for the amountof antibiotic released, in an isotonic phosphate buffer of pH 7.4, at37° C., at the end of 24 hours, to be as least equal to 20 percent ofthe initial amount, for a film having an initial thickness of 0.3 mm,and wherein said amounts are sufficiently low for said amount releasedbeing less than 70 percent of the initial amount.
 13. The pharmaceuticalcomposition of claim 1 wherein said film has a thickness in the range of0.05-1 mm.
 14. The pharmaceutical composition of claim 1 wherein saidfilm is provided with a plurality of perforations.
 15. Thepharmaceutical composition of claim 14 wherein the surface area of saidperforations represents from 10 to 70 percent of the total surface areaof said film.
 16. The pharmaceutical composition of claim 1 wherein saidwater-soluble antibiotic in the form of particles have a size rangingfrom 0.01 to 50 μm.
 17. The pharmaceutical composition of claim 1wherein said antibiotic is present in the form of a pharmaceuticallyacceptable salt.
 18. A process for preparing an implantable andbioresorbable pharmaceutical composition in the form of a powder, saidcomposition comprising poly(lactic acid) and an antibiotically effectiveamount of at least one water-soluble antibiotic in the form of particlesof controlled size less than 100 μm, said antibiotic being dispersedhomogeneously in an amorphous poly(lactic acid) matrix, said processcomprising grinding a homogeneous dispersion of said antibiotic in saidamorphous poly(lactic acid) matrix having a molecular mass ranging from10,000 to 300,000.
 19. A process for preparing an implantable andbioresorbable pharmaceutical composition in the form of a thin film,said composition comprising poly (lactic acid) and at least onewater-soluble antibiotic in the form of particles of controlled sizeless than 100 μm, said antibiotic being dispersed homogeneously in anamorphous poly(lactic acid) matrix, said process comprising admixingsaid amorphous poly(lactic acid) having a molecular mass greater than20,000 with an amorphous poly(lactic acid) having a molecular mass lessthan 5,000.
 20. The process of claim 19 further comprising mixing saidwater-soluble antibiotic particles and said amorphous poly(lactic acid)matrix in a solvent of a polymer wherein said antibiotic is insoluble,said solvent being evaporated and the resulting composition being groundor calendered.
 21. The process of claim 20 wherein said mixing compriseskneading said at least one water-soluble antibiotic in the form ofparticles with said amorphous poly(lactic acid) to produce a film, andcalendering said film.